(Applicant's Abstract) The pathogenesis of idiopathic pulmonary fibrosis is charactenized by an intense inflammatory response with accompanying fibroproliferation and deposition of extracellular matrix. The initial stimulus for inflammatory cell recruitment and the mechanisms responsible for the perpetuation and evolution of chronic inflammation, granulation tissue formation, and fibrosis have not been fully elucidated. While IL-13, a Th2 cytokine, has been shown to have direct effects on fibroblasts that supports fibroproliferation it is also a potent inducer of a novel CC chemokine, CIO, which is chemotactic for mononuclear phagocytes. The macrophage/mononuclear phagocyte has been shown to have a pivotal role in the pathogenesis of pulmonary fibrosis, serving as an important source of growth factors that regulate extracellular matrix synthesis. We hypothesize that the cytokine pathway of IL-13 to C1O promotes pulmonary fibrosis via a mechanism that is independent of the direct effect of IL-13 on fibroblasts. The expression of IL-13 and its receptor leads to the induction of C10, which promotes recruitment of a specific population of pro-fibrotic macrophages. The specific aims are as follows: 1)A. To characterize the expression and regulation of C1O during the pathogenesis of bleomycin-induced pulmonary fibrosis. B. To determine the relative and specific contributions of IL-13 and CIO to the development of pulmonary fibrosis. 2) To compare and contrast the disparity between ligand/receptor expression of IL-4/IL4R and IL-13/IL-13R as they relate to the induction of CIO, and the subsequent development of pulmonary fibrosis. 3) To assess IL-13/IL-13R signal transduction pathways that lead to the induction of CIO, and the subsequent development of pulmonary fibrosis. 4) To establish that CIO recruits a distinct population of macrophages that induce pulmonary fibrosis. 5) To study the effect of administration of exogenous interferon-gamma to patients with IPF on the balance of Th1/Th2 cytokines and the expression of MIP-18 (human homologue of C1O), and to correlate these findings with clinical, radiological and physiological parameters of disease activity. In this project both the bleomycin and FITC models of pulmonary fibrosis will be used. Techniques to be employed include a variety of molecular, immunological and cellular bioassays. Successful completion of these specific aims will provide insight into a novel pathway for macrophage recruitment that may lead to new therapeutic interventions in IPF.